Drug addiction is a significant health problem nationally and locally. Texas was named as one of 2 sites with highest rate of cocaine-related deaths from 2003 to 2004. In 2004, 34.2 million Americans (12 and over) reported lifetime use of cocaine. Thus treatment of addiction to cocaine is a national health issue. Cocaine craving and relapse to cocaine abuse is a feature of addiction that has devastating consequences even after long periods of abstinence. Factors that trigger this relapse include the presence of drug, drug paraphenalia, or environment associated with previous use of the drug. A brain area implicated in cuebased drug associative behavior is the amygdala. Since cues can trigger craving after long periods of abstinence, long-term changes in neuronal plasticity due to chronic cocaine use are likely. These changes may include the strengthening of certain synapses which may underlie the association between the drug and the context or environment in which drug-taking occurred. Such modifications can be mediated through changes in glutamatergic transmission similar to learning and memory mechanisms. Understanding the mechanisms contributing to the lasting association between the cues and cocaine administration is extremely valuable information since data will be directly applicable to treatments that will focus on targeting mechanisms underlying cocaine-craving and cocaine-associative behaviors. These studies would ultimately provide information that contributes to therapies which produce significantly higher success rates in treating cocaine addiction. Conditioned place preference (CPP) is an animal model measuring cue-induced cocaine associative behavior. We have shown that the activity of the enzyme, phospholipase D (PLD), is increased in the amygdala after cocaine-induced conditioned place preference. The overall goal of the proposed research is to determine the role of PLD in the synaptic changes that occur in cue-induced cocaine associative behavior during withdrawal from chronic cocaine. Two specific aims address this goal: specific aim 1, to characterize the role of amygdala PLD activity and mGluR-linked PLD in CPP and specific aim 2, to determine the mechanism by which the mGluR-linked PLD causes an increase in synaptic strength in the basolateral to central amygdala pathway. In this proposal, I plan to utilize behavioral, electrophysiological, and neurochemical approaches to study glutamatergic transmission in the amygdala of animals exhibiting CPP and undergoing 2 week withdrawal from chronic cocaine administration. [unreadable] [unreadable] [unreadable]